Method of preparing an oral preparation provided on the outer side with an enteric coating, as well as an oral preparation obtained by the method

ABSTRACT

A method of preparing an oral preparation, especially in the form of hard gelatin capsules, tablets or pellets, for use by the administration of drugs or supplementary nutrients for human beings or animals, said preparation on its outer side being provided with an enteric coating which contains or comprises a calcium salt of a polysaccharide. A moisture-resistant layer containing a protein, especially zein, can be provided between the material to be coated and the enteric coating. The enteric coating is formed in situ by spraying the liquid coating substances in a fluidized bed. The present invention also pertains to oral preparations which is prepared by the method.

TECHNICAL FIELD

The present invention relates to a method of preparing an oralpreparation, especially in the form of hard gelatin capsules, tablets,powders or pellets, said preparation on the outer side being providedwith an enteric coating resistant to the acid environment in the stomachand containing or comprising a calcium salt of a polysaccharide, where amoisture-resistant layer containing a protein is provided between thematerial to be coated and the coating applied and optionally also on theouter side of the coating. The method according to the invention ischaracterised in that the enteric coating is formed in a fluidized bed,where both a liquid containing calcium ions and a liquid containing theanion of a soluble salt of a polysaccharide are sprayed onto thematerial to be coated.

BRIEF DESCRIPTION OF THE INVENTION

The oral preparation prepared according to the invention is a solidsubstance, for instance in form of tablets, capsules, pellets, powdersor granules to be used by the administration of drugs or supplementarynutrients for human beings or animals, a coating in form of an entericfilm being applied onto said substance. To be more precise, a coating isapplied onto the solid substance, said coating being of such a naturethat upon administration to a human being or an animal said coatedsubstance is substantially unaffected by chemical, enzymatic or otherconditions prevailing in the stomach while said substance passes throughthis portion of the digestive system. Subsequently, the substance is,however, in the process of dissolution or is disintegrating in anothermanner in the intestinal canal with the result that the drug orsupplementary nutrients contained in the solid substance are released.Such preparations are also known as for instance "gastro-resistant","entero-soluble", "enterically coated", or simply "enteric"preparations.

Many situations apply where it is very important or at least advisableto provide an enteric film coating on preparations to be orallyadministered.

Such situations are for instance the following:

(1) It can be essential to ensure that a substance, such as a solidsubstance, contained in the preparation remains intact until it reachesthe absorption site in the intestinal canal without having beensubjected to a previous disintegration in the stomach. Thus, severaldrugs of major medicinal importance, such as some antibiotics and someantiinflammatory and antineoplastic agents are easily and quicklydecomposed under the chemical and enzymatic conditions or otherconditions prevailing in the gastric juices of human beings and animals,whereby these drugs lose their therapeutical effect before they reachthe absorption site. Therefore it is necessary to ensure that such drugsfor oral administration are able to resist the passage through thestomach in such a manner that they can remain intact until they reachthe intestinal canal and without losing the desired effect. Preparationsare also known which contain live (such as freeze-dried) bacteria, suchas Lactobacillus acidophilus, which cannot survive the low pH-values inthe stomach. Such live bacteria are used for the prevention or treatmentof stomach infections.

(2) It can be necessary to protect persons using drugs against dyspepticadverse effects, such as ulcerogenic effects related to the taking in ofdrugs such as acetylsalicylic acid (which is widely used as an analgeticand also increasingly used for the prevention or therapeutical treatmentof cardiovascular diseases), sodium chloride (which for instance is usedinstead of physiological salt), potassium chloride (which is orallyadministered in connection with treatment with diuretics or as areplacement of sodium chloride) or ammonium chloride (which for instanceis used for the treatment of metabolic baseosis).

(3) A demand is found in obtaining a high local concentration of forinstance an antiinflammatory agent or a digestive enzyme in a specificlocation in the intestinal system in order to provoke a specific, localeffect.

(4) Furthermore, it can be important to encapsulate a substance havingan unpleasant taste or smell or which at release in the stomach can benauseating or cause other undesired effects in order to ensure that saidsubstance is not released until it has passed the stomach whether or notthe substance in question is disintegrated by the gastric juices.

The agents previously used for this purpose include polyvinylacetate-phthalate, methacrylacid ester derivatives, such as "Eudragit",and hydroxypropylmethyl cellulose derivatives. Some of these agents havebeen accepted for use as enteric films for the coating of drugs, but thephysiological effect resulting from administration for a long time ofsuch agents is generally unknown, and only a few of these agents havebeen accepted for an enteric coating of foodstuffs or over-the-counterdrugs and supplementary nutrients.

Thus a demand exists for providing a safe and reliable enteric coatingto be used in connection with drugs and supplementary nutrients for oraladministration, said coating being prepared from ingredients havingwell-researched physiological properties and a good compatibility. Thisdemand is met by the present invention, because the method according tothe invention has the effect that on the outer side of the oralpreparation an enteric coating is provided, said coating being resistantto the acid conditions prevailing in the stomach and containing orcomprising a calcium salt of a polysaccharide, especially calciumpectinate or calcium alginate. Freeze-dried lactic acid bacteria are asalready mentioned sensitive to the low pH-values of the magnitudeprevailing in the stomach of human beings and animals. It is thereforenecessary to protect the bacteria against the effect of the lactic acidwhile the preparation is passing through said stomach. The latter isaccording to the invention accomplished by coating the preparation, suchas capsules, tablets, powders or pellets, with a coating which isinsoluble in acid, but soluble under the neutral or slightly alkalineconditions prevailing in the small intestine. Concerning thepH-conditions in the stomach-intestinal system reference is made to D.F. Evans et al., Gut 29, 1035-1041 (1988), J. Fallingborg et al., J.Pediatr. Gastroenterol. Nutr. 11(2), 211-214 (1990) and J. B. Dressman,Pharm. Res. 3 (3), 123-131 (1986).

Many disintegrating processes are accelerated by the presence ofmoisture, which has for instance been determined by stability tests withtablets and capsules. As far as freeze-dried bacteria are concerned itis a fact that the survival of many species depends highly on dryconditions.

Therefore a moisture-resistant layer containing protein is providedbetween the material to be administered, such as a drug or asupplementary nutrient, and the enteric coating. Such amoisture-resistant, water-stopping layer can furthermore be placed onthe outer side of the preparation, i.e. on the surface of the entericcoating. A particularly suited protein for this purpose is zein, whichis only soluble in 85 vol % aqueous alcohol. The low water contentrenders this solvent suited because the solvent of the protein must notcontain too much water as water might otherwise be transferred to thematerial to be administered.

The use of polysaccharides capable of undergoing a cross-linking bymeans of cations is known from a number of publications. ThusJP-A2-04036159 describes a soft capsule, which among other thingscontain pectin and calcium. Soft capsules present, however, limitedapplications because they are not suited for use for instance inconnection with live bacteria.

JP-A2-04027352 describes also soft capsules containing polysaccharidescross-linked by means of calcium ions. These soft capsules are used forhealth food products and are produced by a calcium salt and one or morewater-soluble polysaccharides being mixed into a film substratecomprising gelatin and a plasticizer, in a rotating apparatus for theproduction of capsules.

CN Patent Application No. 87-101114 deals with a method of coatingtablets, where the coating is performed in a coating pan by means ofpowdered sodium alginate in combination with a syrup followed by theapplied layer being treated with a calcium chloride solution. Thecoating in a coating pan is, however, a process encumbered with somedraw-backs, such as a long processing period, high moisture, and thenecessity of using a specially trained staff, and this process is notsuited for coating hard gelatin capsules.

A method of coating tablets with calcium alginate is described in DrugDevelopment and Industrial Pharmacy 20(3), 378-394 (1994). The tabletsare immersed into an aqueous solution of sodium alginate, said tabletscontaining calcium acetate disintegrating and forming a cross-linkingwith the alginate while forming a coating on said tablets. A draw-backis, however, found in the tablets being exposed to water, and in theresulting coating not being smooth. Moreover, the method cannot be usedon capsules, but only on tablets.

The method according to the invention overcomes these draw-backs.

A method related to the method according to the present invention isdisclosed in Journal of Controlled Release 27 (1993), 149-156. However,the object of the coating according to this citation is to achieve a pHindependent release of the drug. The enteric coating according to theinvention aims at achieving the opposite effect, i.e. the release of thedrug being dependent on the pH value. More specifically, the purpose isat acidic pH values to achieve protection against intrusion of liquidinto the preparation or protection against exudation of substance fromthe preparation, whereas at neutral or weakly basic pH values a quickrelease of the substance is desired. This objective is not met with thecoating disclosed in the above citation.

By the method according to the invention, the enteric coating is asmentioned formed in a fluidized bed where a liquid containing calciumions and a liquid containing the anion of a soluble salt of apolysaccharide are sprayed onto the material to be coated. The coatingis performed in a fluidizing apparatus equipped with two or more nozzlesfor the spraying of the liquids, the enteric coating being formed insitu by a reaction between the content of one liquid of polysaccharideanions and the content of the other liquid of Ca²⁺ ions.

Thus the apparatus used employs at least two nozzles, but as threedifferent liquids are used an advantage is found in providing theapparatus with three nozzles because a change from the zein solution toan aqueous solution otherwise requires a preceding cleaning of theentire hose system by means of an aqueous alcohol in order to avoid aclogging.

The invention is illustrated in greater detail by means of the followingExamples:

EXAMPLE 1

An enteric film coating is formed on capsules and tablets in afluidizing apparatus with three nozzles (EB Laboratorie-Coater fromEB-Teknik, Borup, DK). The coating comprises three layers: One innerlayer, an intermediary layer, and an outer layer.

Three suspensions of the following compositions are applied:

    ______________________________________                   %    ______________________________________    Suspension 1    Zein             8.34    Stearic acid     4.2    Olive oil        4.2    Ethanol, 96%     70.0    Purified water   13.26    Suspension 2    Sodium alginate  4    Magnesium stearate                     0.25    Olive oil        0.375    Purified water   95.375    Suspension 3    Calcium gluconate                     10    Purified water   90    ______________________________________

For every cm² tablet or capsule, the following amounts of the abovesuspensions are applied:

    ______________________________________           Nozzle 1  Nozzle 2    Nozzle 3    ______________________________________    Inner layer             15 mg susp. 1    Intermediary         80 mg susp. 2                                     22 mg susp. 3    layer    Outer layer              5 mg susp. 1    ______________________________________

Inner layer: Suspension 1 is sprayed thereon

Intermediary layer: The suspensions 2 and 3 are sprayed through theirrespective nozzles.

Outer layer: Suspension 1 is sprayed thereon.

EXAMPLE 2

In an apparatus as described in Example 1 a coating is performed of hardgelatin capsules in a fluidized bed by means of 3 nozzles, 1 nozzlebeing used for each of the following suspensions.

    ______________________________________                    %    ______________________________________    Zein suspension    Zein              8.34    Stearic acid      4.20    Olive oil         4.20    Ethanol, 96%      70.00    Purified water    13.26    Alginate suspension    Sodium alginate   4.00    Magnesium stearate                      0.25    Olive oil         0.375    Purified water    95.375    Ca-gluconate suspension    Calcium gluconate 10.00    Purified water    90.00    ______________________________________

Initially, the capsules are heated to a temperature of 38° to 43° C.,whereafter a layer of the zein suspension is applied, which counteractsthe penetration of water during the further coating. Input temperature:50° to 60° C.; output temperature: 39° to 43° C. Nozzle pressure:approximately 4 bar.

In the following step the capsules are provided simultaneously through 2nozzles with a layer of the alginate suspension and a layer of thecalcium gluconate suspension. Input temperature: 65° to 75° C.; outputtemperature: 39° to 43° C. Nozzle pressure: approximately 4 bar.

Finally the capsules are provided with yet another layer of the zeinsuspension. Input temperature: 50° to 60° C.; output temperature: 39° to43° C. Nozzle pressure: approximately 4 bar. As a result, a tightsurface is obtained.

After the coating, the capsules are cooled.

EXAMPLE 3

The following test illustrates that the protein zein counteractspenetration of water into the material to be coated.

An enteric film coating is applied to hard gelatin capsules in anapparatus as mentioned in Example 1. The coating comprises four layers:One inner layer, 2 intermediary layers (2 and 3), and an outer layer.

Three suspensions of the following compositions are applied:

    ______________________________________                   %    ______________________________________    Suspension 1    Zein             8.34    Stearic acid     4.20    Olive oil        4.20    Ethanol, 96%     70.00    Purified water   13.26    Suspension 2    Sodium alginate  4.00    Magnesium stearate                     0.25    Olive oil        0.375    Purified water   95.375    Suspension 3    Calcium gluconate                     10.00    Purified water   90.00    ______________________________________

For every cm² capsule surface the following amounts of the abovesuspensions are applied:

    ______________________________________           Nozzle 1  Nozzle 2    Nozzle 3    ______________________________________    Inner layer             5 mg susp. 1    Layer 2  10 mg susp. 1                          8 mg susp. 2    Layer 3              80 mg susp. 2                                     22 mg susp. 3    Outer layer             5 mg susp. 1    ______________________________________

Input temperature: 50° to 70° C.; output temperature: 40° to 42° C.Nozzle pressure: approximately 4 bar.

As an expression of the counteracting of water penetration into thecapsules, the so-called aw value is used:

    ______________________________________                  aw    ______________________________________           Before coating                    0.14           After coating                    0.26    ______________________________________

By way of comparison, the following amounts of the above suspensions areinstead applied per cm² of capsule surface:

    ______________________________________           Nozzle 1  Nozzle 2    Nozzle 3    ______________________________________    Inner layer             15 mg susp. 1                         12 mg susp. 2    Intermediary         80 mg susp. 2                                     22 mg susp. 3    layer    Outer layer              5 mg susp. 1    ______________________________________

in such a manner that the inner layer contains both zein and sodiumalginate suspensions. The following result applies:

    ______________________________________                  aw    ______________________________________           Before coating                    0.14           After coating                    0.40    ______________________________________

Three nozzles are used in the apparatus in order to avoid a cleaning ofthe hose system when changing from zein solution to an aqueous solution.The use of only two nozzles would furthermore necessitate a thoroughcleaning of the hose system when changing from calcium gluconate tosodium alginate due to the risk of formation of insoluble calciumalginate.

We claim:
 1. A method of preparing an oral preparation to be used forthe administration of drugs or supplementary nutrients for human beingsor animals, the outer surface of said preparation being provided with anenteric coating which is resistant to the acid environment in thestomach and which contains or comprises a calcium salt of apolysaccharide, said method comprising the following steps:(a) applyinga moisture-resistant layer on the material to be coated by spraying aliquid containing a protein and stearic acid on the material, (b)providing an enteric coating upon the moisture-resistant layer byspraying in a fluidized bed, where a liquid containing calcium ions andanother liquid containing the anion of a soluble salt of apolysaccharide are applied from separate nozzles, and (c) optionallyapplying a second moisture-resistant layer containing a protein upon theenteric coating by spraying in situ.
 2. A method as claimed in claim 1,wherein the coating is performed in a fluidizing apparatus equipped withtwo or more nozzles for the spraying of the liquids, and that theenteric coating is formed in situ by a reaction between the content ofone liquid of polysaccharide-anions and the content of the other liquidof Ca²⁺ ions.
 3. A method as claimed in claim 1 wherein the calcium saltis calcium pectinate or calcium alginate.
 4. A method as claimed inclaim 1, wherein the protein is zein.
 5. An oral preparation to be usedfor the administration of drugs or supplementary nutrients for humanbeings or animals, said preparation on the outer side being providedwith an enteric coating, wherein the oral preparation is prepared by amethod as claimed in claim
 1. 6. A method according to claim 1, whereinthe oral preparation is in the form of a hard gelatin capsule, tablet,powder or pellet.
 7. The oral preparation according to claim 5, in theform of a hard gelatin capsule, tablet, powder or pellet.